When hamsters are treated neonatally with the synthetic estrogen, diethylstilbestrol (DES), their uteri consistently exhibit a severe hyperplastic/neoplastic response to estrogen in adulthood. One of two alternative working hypotheses should explain this phenomenon: 1) Direct Action - The cellular physiology and/or composition of the neonatal hamster uterus is directly and permanently altered by the DES insult such that the adult organ's overall proliferative response to estrogen becomes atypical, or 2) Indirect Action - Uterotrophic activity is mediated by estrogen primarily through or in conjunction with other unidentified factors, and neonatal DES treatment permanently alters the level or functional activity of such factors. Testing these hypotheses will begin (Specific Aim # 1) by monitoring the morphogenesis of neonatal uteri from control and DES-treated donor animals that are transplanted into the contralateral cheek pouches of control and DES-treated mature hosts that are either left intact, estrogen-deprived or estrogen-replaced. To confirm and extend the findings (Specific Aim #2), homotypic and heterotypic recombination of uterine stroma and epithelium from control and DES-treated animals will be performed and their morphogenesis will be studied: a) in vitro using media supplemented with uterine tissue extracts and/or serum from the same host groups used in Specific Aim # 1 and b) in vivo (within the cheek pouch, using the same host groups as in Specific Aim #l. Lastly (Specific Aim #3), Northern blot analysis will be used to consider the possibility that altered expression of two proto-oncogenes (c-myc and c-fos) may be involved in the atypical estrogen responsiveness of uteri in neonatally DES-exposed hamsters. Because this combination of approaches relies on few, if any, a priori assumptions and accommodates both in vivo and in vitro observations, firm conclusions should be reached about which alternative hypothesis is most valid. Such information should contribute significantly to the long-term objective of understanding how estrogen regulates uterine growth and morphogenesis. This objective is biomedically important because: 1) successful conception and gestation demands normal uterine form and function, and 2) estrogen-dependent uterine neoplasms are responsible for considerable morbidity and mortality in contemporary American society.